Principal Investigator/Program Director (Last, first, middle): O'Neill, Michael RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 08-24-2006 Animal Welfare Assurance Number A3124-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 9047-summary.pdf Mime Type: application/pdf 7. * Project Narrative 5269-Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 608-8Biblio.pdf Mime Type: application/pdf 9. Facilities &Other Resources 8272-ResourcesMO.pdf Mime Type: application/pdf 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): O'Neill, Michael Summary Genomic imprinting is a form of epigenetic gene regulation that leads to one of the two parental copies of a gene being inherited in a transcriptionally silent state. Mutations within imprinted loci disrupt normal patterns of growth and development, underlying specific cognitive defects and predisposition to certain cancers. The molecular mechanisms by which imprinted genes are programmed to be silent, and how genomic imprints are propagated each generation are not well understood. Insights gained in the study of imprinted gene regulation, however, have been indispensable to the current concept of epigenetic gene regulation in general. A new and somewhat unexpected finding in the field of genomic imprinting is the discovery of a cluster of imprinted genes on the mammalian X chromosome. Unique features about the ontogeny and global control of gene expression on the X suggest that the epigenetic control of X-linked imprinted gene expression may be dramatically different from that of imprinted autosomal genes. The primary goal of the work proposed in this application is to fully characterize the epigenetic regulatory factors that influence transcription of the newly discovered cluster of X- linked imprinted genes. We will first perform experiments to determine if the regulation of X- linked imprinted genes is influenced by X chromosome inactivation and DNA methylation. We will then perform chromatin immunoprecipitation experiments using microarray technology to determine the factors that regulate expression at this locus. Finally, we will produce mutant mice by gene targeting that lack certain elements that preliminary results suggest are